Prescription for Trouble

When the pharmaceutical giant Merck pulled its blockbuster pain medication Vioxx off the market in late September, it became the largest prescription drug recall in history.

The company says it took immediate action after a new study showed that Vioxx doubled the risk of heart attacks and strokes in some patients.

However, according to internal Merck documents 60 Minutes has seen, and interviews with outside scientists, Merck had concerns that Vioxx could possibly cause cardiovascular risks long before it was pulled off the market.

Some 20 million Americans took Vioxx in the five-and-a-half years it was being sold. It may have contributed to thousands of heart attacks and sudden deaths. Three government investigations are now underway to determine just how and why Vioxx became a prescription for trouble. Correspondent Ed Bradley reports.

When Vioxx first hit the market under a barrage of TV commercials, it was hailed by Merck as a miracle drug.

It was one of a new class of drugs called COX-2 inhibitors that could reduce all kinds of pain, especially arthritis, without causing serious gastrointestinal discomfort and bleeding – a risk seen in older drugs like aspirin, Aleve and Advil.

With annual sales of about $2.5 billion, Vioxx was one of the most successful new drugs ever. It was prescribed to people like 39-year-old Janet Huggins, who had been diagnosed with early stage rheumatoid arthritis.

According to her medical records, Huggins was in otherwise excellent health. But that was until Sept. 25, when she died of a sudden heart attack – less than a month after she started taking Vioxx. She was buried on the very day Merck took Vioxx off the market. Huggins’ husband Monty is suing Merck, holding the company responsible for her death.

“The morning of her funeral, I had just gotten dressed and my sister walked in and told me that she had just seen on the news that Vioxx had been pulled from the market. And when she told me that, I can’t explain what hit me,” says Monty Huggins. “I dropped straight to the floor. It was just a shock, because this is a 39-year-old female that’s in good shape and is healthy and she’s got a heart attack.”

He says that if the drug had been taken off the market a month earlier, “I believe my wife would be here.”

But was it Vioxx? Merck says it believes that many of the deaths being attributed to Vioxx could be explained by any number of other causes. The company insists it has acted responsibly, saying it withdrew Vioxx as soon as it received what it says was surprising data from a clinical trial it was conducting, called the APPROVe (Adenomatous Polyp Prevention on VIOXX) study, designed to determine if Vioxx could prevent colon polyps.

Instead, Merck found something potentially worse: Patients taking Vioxx for longer than 18 months were twice as likely to suffer a heart attack or stroke than those taking a placebo.

Merck declined a request from 60 Minutes for an on-camera interview, but CEO Raymond Gilmartin explained the company’s decision in a Sept. 30 news conference: “We’re taking this action because we believe it best serves the interest of patients. We believe that it would have been possible to continue to market Vioxx with labeling that would incorporate these new data. However, given the availability of alternative therapies, and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take.”

Merck maintains that the APPROVe study provided the first clear evidence that Vioxx was linked to heart attacks and strokes. But attorney Andy Birchfield is spearheading an all-out legal assault against Merck.

Birchfield met this week with hundreds of plaintiff’s lawyers from across the country to coordinate their efforts in lawsuits they will soon file against Merck on behalf of more than 10,000 people who it’s claimed were harmed or killed by Vioxx.

“Merck knew, even before this drug went on the market, that there could be a significant increase in cardiovascular risk. To say that the APPROVe study was the first indication that they had of a risk is absolutely untrue,” says Birchfield. “You know, they had warning sign after warning sign, study after study, that suggested a significant, a substantial increase in risk.”

Why would they do this? “Merck needed a blockbuster drug. They needed, they had drugs that were coming off patent and they needed a – a big revenue source,” says Birchfield.

Merck denies that profits would come before patient safety. In 1999, Merck conducted its biggest clinical trial of Vioxx – a study of 8,000 people called the VIGOR (VIOXX Gastrointestinal Outcomes Research) study. It was designed to determine if Vioxx was safer on the stomach than an older pain medication called Naproxen.

While the VIGOR study found that Vioxx caused fewer gastrointestinal side effects than Naproxen, Vioxx users also had a nearly five-fold increase in heart attacks. Merck attributed the increase to what it believed was Naproxen’s ability to protect the heart, not to any problem with Vioxx.

However, an internal Merck email written by the company’s research president in March 2000 – the day he learned about the results of the VIGOR study, and nearly a year after the drug came on the market – said that heart problems “are clearly there.” And he said: “It is a shame, but it is a low incidence and it is mechanism-based as we worried it was.” “Mechanism-based” refers to the molecular structure of the drug.

Plaintiff’s attorneys cite that and other Merck internal memos and e-mails as far back as 1996, which they say show some Merck scientists anticipated a higher rate of heart problems. Merck says those emails reflect only hypothetical concerns, and that there was not enough evidence at the time to prove that Vioxx increased the risk of heart problems.

Dr. Eric Topol, chief of cardiovascular medicine at the Cleveland Clinic, was Merck’s first and most persistent critic. In 2001, he conducted a statistical analysis of all the available data about Vioxx. His study was published in the Journal of the American Medical Association.

What did his study – which came out after the VIGOR study – find?

“That study, which looked at all the data available for the both the medicines of these COX-2 inhibitors and all other medicines, including aspirin, that were available, showed a very substantial worrying risk of heart attacks and strokes – across the board – from the VIGOR trial and about Vioxx,” says Topol.

Topol examined data from a 1998 Merck clinical trial called Study “090”, which was never published. Among 978 patients studied, serious cardiovascular events, including heart attack and stroke – were found about six times more often in patients taking Vioxx than in patients taking another arthritis drug or a placebo.

Merck says that study was too small and not statistically significant enough to be able to draw any conclusions, but Topol maintains that, combined with the VIGOR trial, it showed that by the year 2000, there was solid evidence that Vioxx was not safe. Merck says Topol’s methodology was flawed and disputed his findings.

“Merck took on any study that questioned the safety of Vioxx, with respect to the heart attacks and strokes. Any study,” says Topol.

“But can’t they say on the other hand, ‘OK, there are always dissenters. We’ve got these other studies that say the drug is fine,’” asks Bradley.

“Whenever you find a problem and you’re thinking maybe it’s not a problem, you want to see if there’s independent replication,” says Topol. “So if you have Study ‘090′, and you want to discount that somehow, then you have VIGOR
. You got two trials now. You have essentially lightning striking twice. That’s independent replication, that’s really serious confirmation. This is unequivocal. This is a problem.”

Did Topol ever talk to Merck officials about this? “I tried,” he says. “I called Mr. Gilmartin, the CEO, and the director of research, Dr. Peter Kim, on multiple occasions, asking to discuss this. But the calls were never returned.”

Merck says while it was concerned about the cardiovascular risks seen in the VIGOR study, it was not conclusive evidence that Vioxx caused heart attacks. And the company points out that it conducted a number of studies before and after FDA approval, which did not show the heart risk seen in the VIGOR study.

As safety questions about Vioxx continued to be raised in medical journals, Merck continued its $500 million advertising campaign. The company had developed a training document 60 Minutes obtained called “Dodge Ball Vioxx,” which instructs Merck sales representatives how to promote the drug to physicians.

The manual consists of a 12-page list of obstacles. These are questions a doctor could pose, such as “I am concerned about the cardiovascular effects of Vioxx?”

A former Merck sales representative told 60 Minutes how she was trained to answer that question. She asked that we not use her name, and that we alter her appearance and voice.

“We were supposed to tell the physician that Vioxx did not cause cardiovascular events, that instead, in the studies, Naproxen has aspirin-like characteristics which made Naproxen a heart-protecting type of drug where Vioxx did not have that heart-protecting side,” she said.

The FDA says there is no conclusive evidence that Naproxen protects the heart. Merck told 60 Minutes the use of the word “dodge” was unfortunate and that the company instructed its sales force to be honest and straightforward about Vioxx.

The former sales representative we spoke to told us she feels the company betrayed her: “I put my reputation on the line. I gave my physicians my word that Vioxx was a safe, effective product and it’s been pulled from the market because it was killing people.”

Merck’s marketing campaign didn’t sit well with the FDA, which sent a warning letter to the company in September 2001, saying that sales representatives “have engaged in false or misleading promotional activities,” and that the company’s promotional campaign “minimizes the potentially serious cardiovascular findings” about Vioxx.

Dr. Janet Woodcock, acting deputy commissioner of the FDA, says her agency took appropriate action based on the Vioxx studies. “Certainly we were concerned,” says Woodcock.

“If you were concerned, you weren’t concerned enough to pull it off the market,” says Bradley.

“That’s correct. Here we had a new benefit, and I think it’s important to recognize that there are many thousands of deaths every year from the gastrointestinal toxicity of the anti-inflammatory agents,” says Woodcock.

“This is a serious problem,” she continues. “On the other hand, we had a red flag for cardiovascular events. But we didn’t know what it meant. There were other studies that did not show this increase with the ordinary dose of Vioxx. And more study was needed to understand what this meant.”

Looking back, was there anything the FDA should have done?

“I think we were on top of the case here,” says Woodcock. “And we did what we could to get all the evidence together and keep information flowing.”

The FDA says Merck made certain changes – including changing the Vioxx package label in 2002 disclosing cardiovascular risks. But that was more than a year after the FDA asked the company to do so.

Sen. Charles Grassley, chairman of the Senate Finance Committee, which is investigating Merck and the FDA, says the FDA dropped the ball on Vioxx.

“With Vioxx being withdrawn by the company, with the prospect that – that people may have died because this drug was not safe, you just wonder where FDA has been,” says Grassley. “Because there were red flags about this drug both within the FDA and within the Merck organization for a long period of time, and you wonder why with all the questions being raised it takes five years – for a drug to be pulled.”

Less than two weeks ago, the British medical journal The Lancet published a study that concluded, based on an analysis of previous studies, Vioxx should have been “withdrawn several years earlier.”

While Merck disputes that finding, Topol says there is a lesson to be learned. “In trying for now two decades in my career to try to prevent heart attacks and treat heart attacks, to have a medicine that’s causing heart attacks and strokes is something that can’t be tolerated,” says Topol. “These are the two biggest, most important killers in our society. And then it’s important that we never have something like this happen again.”

Congressional hearings are set to begin later this week into the Vioxx affair. The U.S. Justice Department is conducting an investigation, and the Securities and Exchange Commission is looking into the conduct of Merck. The company’s stock value has fallen by roughly $30 billion since Vioxx was pulled off the market.

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